In this application we propose to synthesize libraries based on a variety of different structures. In general scaffolds based in structures that have promise as active compounds will be synthesized. In all but one of the cases, we will then use a variety of chemistry including palladium catalyzed coupling to derivatize these platforms. We have already developed routes to thioxanthenone dioxides and have shown that they can be easily modified with Suzuki couplings and nucleophilic substitution. A modification of the Robinson tropinone synthesis will be used to synthesize tropane scaffolds containing different functionality, as well as tropinone derivatives where pharmacophores are attached to the 3.2.1 scaffold. In conjunction with a project to synthesize compounds with activity against anthrax edema factor, we have found that cyclohexanone and cyclopentanones containing imidazole and other nitrogen heterocycles have micromolar activity. Consequently, we propose to synthesize libraries consisting of cyclic ketones that have a variety of pharmacophores attached. The reaction between Fischer carbene complexes and alkynes can produce a number of different structure types. We plan to synthesize libraries of quinones and cyclohexadienones using this chemistry. Depending on the desired library size and quantity of material desired, we will use carbene complexes attached to polymer supports as well as solution methods. While the types of scaffolds are highly varied, there are number of the same reactions and reagents that will be used in their synthesis. Palladium catalyzed coupling reactions of aryl and vinyl boronic acids and esters will be used extensively. Additionally, a number of the scaffolds will utilize ester functionality as an attachment point for different pharmacophores. A fundamental advantage of choosing libraries that are structurally different but use similar chemistry is that it is highly likely that they will have significantly different activity profiles and yet we can build them efficiently using common chemical reactions.